Endothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria.
Endothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria.
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DOI：
10.1038/s41418-022-01042-8
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发表时间：
2023-01
影响因子：
12.4
通讯作者：
Samson, Andre L.
中科院分区：
文献类型：
--
作者：
Bader, Stefanie M.;Preston, Simon P.;Saliba, Katie;Lipszyc, Adam;Grant, Zoe L.;Mackiewicz, Liana;Baldi, Andrew;Hempel, Anne;Clark, Michelle P.;Peiris, Thanushi;Clow, William;Bjelic, Jan;Stutz, Michael D.;Arandjelovic, Philip;Teale, Jack;Du, Fashuo;Coultas, Leigh;Murphy, James M.;Allison, Cody C.;Pellegrini, Marc;Samson, Andre L.
半胱天冬酶-8从死亡受体配体（如肿瘤坏死因子）转导信号，以驱动包括炎症、细胞增殖或细胞死亡在内的有效反应。这是一种发育必需的功能，因为在子宫内内皮Caspase-8的缺失会导致胚胎发生期间的全身循环衰竭。内皮Caspase-8是否也是成年期心血管通畅所必需的尚不清楚。为了解决这个问题，我们使用了一种诱导型Cre重组酶系统，在6周龄的条件基因靶向小鼠中删除内皮细胞Casp 8。广泛的全身血管基因靶向已得到证实，但主要表型是仅在小肠内的致命出血性病变。这些肠道病变的出现并不是对内皮细胞Caspase-8缺陷的适应不良免疫反应，而是依赖于微生物细胞和肿瘤坏死因子受体信号传导的异常Toll样受体感应。这种致死表型在缺乏坏死性凋亡细胞死亡效应物MLKL的复合突变小鼠中被阻止。因此，与其在胚胎发生过程中的全身作用不同，我们的数据显示，失调的微生物和死亡受体信号传导在成年小鼠小肠中独特地达到顶峰，在内皮Caspase-8丧失后释放MLKL依赖性坏死性出血。这些数据支持Caspase-8在面对微生物入侵时保持肠道血管完整性方面的关键作用。
Caspase-8 transduces signals from death receptor ligands, such as tumor necrosis factor, to drive potent responses including inflammation, cell proliferation or cell death. This is a developmentally essential function because in utero deletion of endothelial Caspase-8 causes systemic circulatory collapse during embryogenesis. Whether endothelial Caspase-8 is also required for cardiovascular patency during adulthood was unknown. To address this question, we used an inducible Cre recombinase system to delete endothelial Casp8 in 6-week-old conditionally gene-targeted mice. Extensive whole body vascular gene targeting was confirmed, yet the dominant phenotype was fatal hemorrhagic lesions exclusively within the small intestine. The emergence of these intestinal lesions was not a maladaptive immune response to endothelial Caspase-8-deficiency, but instead relied upon aberrant Toll-like receptor sensing of microbial commensals and tumor necrosis factor receptor signaling. This lethal phenotype was prevented in compound mutant mice that lacked the necroptotic cell death effector, MLKL. Thus, distinct from its systemic role during embryogenesis, our data show that dysregulated microbial- and death receptor-signaling uniquely culminate in the adult mouse small intestine to unleash MLKL-dependent necroptotic hemorrhage after loss of endothelial Caspase-8. These data support a critical role for Caspase-8 in preserving gut vascular integrity in the face of microbial commensals.
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DOI：
10.1038/nrmicro3552
发表时间：
2016-01
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Donaldson GP;Lee SM;Mazmanian SK
通讯作者：
Mazmanian SK
影响因子：
16.6
作者：
Duvallet C;Gibbons SM;Gurry T;Irizarry RA;Alm EJ
通讯作者：
Alm EJ
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
7.2
作者：
Annibaldi, Alessandro;Walczak, Henning
通讯作者：
Walczak, Henning
影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR